The papillomaviruses cause benign and malignant lesions of squamous epithelia in higher vertebrates. The complete lytic cycle of these viruses (including late gene expression) occurs only in the differentiated cells of the squamous epithelium. Malignant lesions and infected cells in culture do not produce virus. We have used bovine papillomavirus type 1 (BPV-l) as a model system for the study of papillomavirus late transcription and its control. Transcriptional mapping data indicates that the mRNAs, which encode both the major and minor capsid proteins, are expressed from a strong viral transcriptional promoter (called the late promoter) which is active only in productively infected epithelium. Our studies have also shown that there are multiple mechanisms which inhibit BPV-1 late transcription in nonproductively infected cells. Nuclear run-off analysis of BPV-1 transcription in transformed C127 cells indicates that transcription of the BPV-1 genome is attenuated greater than tenfold between the early and late polyadenylation sites, effectively favoring the use of the early polyadenylation site over the late polyadenylation site. A series of cell lines transformed by BPV-1 genomes containing mutations in the late region have been established to identify the cis elements responsible for transcription termination. Expression vectors have also been used to identify two negative regulatory elements in the BPV-1 late region. One element has been mapped to the 5' portion of the late region. The mechanism of action of this element is currently under investigation. A second negative regulatory element has been mapped to the late 3' untranslated region and inhibits the expression of a heterologous gene when cloned into the 3' untranslated region of that gene. This element most likely inhibits late gene expression in nonproductively infected cells by selectively destabilizing late mRNAs. Several approaches are being used to confirm this model and to determine if late mRNA stability is regulated during keratinocyte differentiation.